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Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs) to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified  NRG1  as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs ( p  = 1.50×10 −5 ), particularly for those encompassing genes ( p  = 5.00×10 −6 ). Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a  NRG3  deletion ( p  = 1.64×10 −3 ). Subsequent follow-up (96 additional patients and 220 controls) on  NRG3  revealed 9 deletions (combined  p  = 3.36×10 −5 ) and 2  de novo  duplications among patients and two deletions among controls. Importantly,  NRG3  is a paralog of  NRG1 . Stratification of patients by presence/absence of HSCR–associated syndromes showed that while syndromic–HSCR patients carried significantly longer CNVs than the non-syndromic or controls ( p  = 1.50×10 −5 ), non-syndromic patients were enriched in CNV number when compared to controls ( p  = 4.00×10 −6 ) or the syndromic counterpart. Our results suggest a role for  NRG3  in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR.

Genome-Wide Copy Number Analysis Uncovers a New HSCR Gene: NRG3